Information notification sample processing system and methods of biological slide processing

ABSTRACT

A sample processing system ( 101 ) that may be automated and methods are disclosed where samples) ( 198 ) are arranged on a carrier element ( 197 ) and a process operation control system ( 171 ) automatically processes the samples) perhaps robotically with an operationally-influential exteriorly-consequential information monitor ( 402 ) or a data capture element ( 414 ). Significant process details as well as operationally-influential exteriorly-consequential information may be monitored and an automatic notice element ( 404 ) may cause notification of a person at some display ( 415 ) that may be remote. Various people may be notified, such as an administrator, a supplier, or a manufacturer of an opportunity for some action such as reagent reordering or the like. A simulated motion display may be included to “watch” simulated operation in real time or long after completion of the actual processing.

This application is the United States National Stage of InternationalApplication No. PCT/US2003/040974, filed Dec. 19, 2003 which claims thebenefit under 35 U.S.C. 119(e) of United States Provisional ApplicationNo. 60/435,601, filed Dec. 20, 2002, each hereby incorporated byreference herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is related to the following U.S. patent applications:U.S. application Ser. No. 10/741,628 filed Dec. 19, 2003; U.S.application Ser. No. 11/156,760 filed Jun. 20, 2005; U.S. applicationSer. No. 11/176,757 filed Jul. 7, 2005; U.S. application Ser. No.10/538,964, the U.S. National Stage of PCT Appl. PCT/US03/40518 filedDec. 19, 2003; U.S. application Ser. No. 10/539,562, the U.S. NationalStage of PCT Appl. PCT/US03/40880 filed Dec. 22, 2003; U.S. applicationSer. No. 10/731,316 filed Dec. 8, 2003; U.S. application Ser. No.10/539,035, the U.S. National Stage of PCT Appl. PCT/US03/40519 filedDec. 19, 2003; U.S. application Ser. No. 10/539,561, the U.S. NationalStage of PCT Appl. PCT/US03/40591 filed Dec. 19, 2003; U.S. applicationSer. No. 10/539,192, the U.S. National Stage of PCT Appl. PCT/US03/41022filed Dec. 22, 2003; U.S. application Ser. No. 10/539,308, The U.S.National Stage of PCT Appl. PCT/US03/40520 filed Dec. 19, 2003; U.S.application Ser. No. 11/168,987, filed Jun. 28, 2005; U.S. applicationSer. No. 11/229,098, filed Sep. 16, 2005; U.S. application Ser. No.11/338,524 filed Jan. 23, 2006; U.S. application Ser. No. 11/338,522filed Jan. 23, 2006; and U.S. application Ser. No. 11/227,270 filed Sep.16, 2005.

TECHNICAL FIELD

This application relates to the field of sample processing systems andmethods of automatically monitoring and notifying of certain informationfor the processing of samples or the process system. The presentinvention may be directed to the automated processing, treatment, oreven staining of samples arranged on carriers, such as slides, and insome embodiments, directed to the continuous or batch processing ofsamples and carriers. Embodiments may further relate to control systemsfor sample processing and data input, acquisition, maintenance, andretrieval for sample processing. Applications to which the presentinvention may especially relate include immunohistochemistry, in-situhybridization, fluorescent in-situ hybridization, special staining, andcytology, as well as potentially other chemical and biologicalapplications.

BACKGROUND

Sample processing in immunohistochemical (IHC) applications and in otherchemical and biological analyses may require one or a number of variousprocessing sequences or protocols as part of an analysis of one or moresamples. The sample processing sequences or protocols may be defined bythe individual or organization requesting an analysis, such as apathologist or histologist of a hospital, and may be further defined bythe dictates of a particular analysis to be performed.

In preparation for sample analysis, a biological sample may be acquiredby known sample acquisition techniques and may comprise, for example inIHC applications, tissues generally or even in some applications one ora plurality of isolated cells, such as in microarray samples, and may bepresented on a sample carrier including but not limited to microscopeslides. Furthermore, the sample may be presented on the carriervariously and potentially in some form of preservation. As one example,a sample such as a layer or slice of skin may be preserved informaldehyde and presented on a carrier with one or more paraffin orother chemical layers infiltrating the sample.

Immunologic applications, for example, may require processing sequencesor protocols that comprise steps such as deparaffinization, targetretrieval, reagent application, and staining, especially for in-situhybridization (ISH) techniques. In some applications, these steps mayhave been performed manually, potentially creating a time-intensiveprotocol and necessitating personnel to be actively involved in thesample processing. Even when performed automatically, there have beeninefficiencies in such systems. Attempts have been made to automatesample processing to address the need for expedient sample processingand a less manually burdensome operation. However, such previous effortsmay have not fully addressed certain specific needs for an automatedsample processing system. Previous efforts to automate sample processingmay be deficient in several aspects that prevent more robust automatedsample processing, such as: the lack of sufficient computer control andmonitoring of sample processing; the lack of information sharing forprocessing protocol and processing status, especially for individualsamples; the lack of practical information input and process definitionentry capabilities; the lack of diagnostic capabilities; and the lack ofreal-time or adaptive capabilities for multiple sample batch processing.

Past efforts at automated sample processing for samples presented oncarriers such as slides, such as U.S. Pat. No. 6,352,861 to VentanaMedical Systems, Inc. and U.S. Pat. No. 5,839,091 to LabVisionCorporation, have not afforded the various advantages and othercombinations of features as presented herein.

One of the various aspects that may be significant to users of automatedprocess systems is that of handling information related to the process,the substances used in processing, or even the process instrumentitself. In this regard, it has often been considered that operators haveto have particular knowledge and skills in order to assure the integrityof the process or instrument or result. Perhaps as a result of thisfact, human error was introduced into the system. The present inventionseeks to reduce such effects to some degree and seeks to provide asystem that may be considered more user, operator, supplier, ormanufacturer friendly.

DISCLOSURE OF INVENTION

The present invention presents an automated sample processing systemthat may greatly improve operation of automated sample processing fromseveral perspectives. It may act to monitor information existingrelative to the sample processing events and materials and mayautomatically inform those in a position to need to know. It also maycapture and store high levels of detail relative to the sampleprocessing events so users, recipients, or even maintenance personnelmay have ready and certifiable access to what occurred. As described,sample processing can be accomplished as disclosed herein. In providingthis disclosure, it should be understood that the various examples anddesigns disclosed for sample processing and other disclosed techniques,are not meant to limit the present invention to any particularembodiment, whether apparatus, method, or otherwise. These descriptionsare provided rather to describe various sample processing techniques ina manner in which the present invention can be understood. Thedescriptions incorporated by reference and the various examples shouldnot be construed to limit the present invention to only such techniques.This disclosure, however, may be understood to incorporate the varioustechniques in the context of the various embodiments of the presentinvention.

The techniques and systems of sample processing are addressed in afashion that may provide the processing of one or more samples or of aplurality of groups of one or more samples in sequential ornon-sequential fashion. Processing of samples may be determined by theprotocol to be followed for each sample or a protocol for multiplesamples. Aspects of the present invention may be especially applicableto sample processing having one or a plurality of processing steps to beperformed on one, a portion, or an entirety of samples, such protocolsidentified in some instances by individual carriers presenting thesamples or by the individual samples themselves. As mentioned, thepresent invention may be especially applicable to immunohistochemistry(IHC) techniques, as well as in-situ hybridization (ISH) and fluorescentin-situ hybridization (FISH), special staining of samples, andmicroarrays; especially techniques incorporating target retrieval or thestaining of samples. Furthermore, embodiments may be directed toprocessing sequences addressing issues of processing control.

Embodiments of the invention may further relate to automated controlsystems for sample processing. Embodiments may also be directed to dataacquisition, input, maintenance, and retrieval for sample processing, aswell as information sharing of processing protocol and processinginformation, and real-time or adaptive capabilities for processing.

To disclose the foregoing and other objects and in accordance with thepurposes of the present invention, as broadly embodied and describedherein, the present invention is characterized in various claims and inexplanatory disclosure. None of these should be understood as limiting.Further, all claims presented at any time are incorporated in thespecification to afford all opportunities of presentation. Claimspotentially to be pursued for some of the initially presented aspects ofthe invention may include any aspects described.

To achieve the foregoing and other objects of invention, and as may befurther disclosed and claimed throughout this description, the inventionmay comprise an automated sample processing system comprising aplurality of drawers, a plurality of sample carrier elements that mayeven be each removably configured with one of the drawers, and anadaptive or other sample processing control system. The sample carriersmay be both movable and removable. The sample processing control systemmay automate the sample processing system such that one or more samplesmay be processed according to one or more protocols, potentiallyindicated by information on slides or otherwise input to the system.This sample processing may comprise one or more sampling protocols andsteps, such as deparaffinization, target retrieval, and staining.

A sensor may be provided in some embodiments that may automaticallyidentify information from one or more samples, sample carriers, orslides. In embodiments, protocol information may be provided or madeavailable by the sample processing control system. The sample processingsystem may then process one or more samples or perhaps slides, or one ormore batches of slides, concurrently, sequentially, or in any othertemporal fashion, potentially in accordance with protocol informationpreviously provided for a sample by a user or other decision maker. Thisinformation can then be made available for use by the sample processingcontrol system. Sample batches or individual slides may even be insertedor removed during processing protocol steps by the control andmonitoring accomplished by the adaptive sample processing controlsystem.

Another embodiment of the present invention that may achieve theforegoing and other objects of invention may comprise a method of sampleprocessing, comprising the steps of: accessing at least one of aplurality of samples or sample drawers, providing at least one samplecarrier or perhaps a sample carrier retainment assembly configured withat least one sample, configuring at least one of the drawers with the atleast one sample carrier, and adaptively processing the sample. The stepof processing or perhaps even adaptive processing may be applied toautomate the processing of samples and may allow for either or bothcontinuous or batch processing of samples or slides. It may also affordmultiple independent sample or slide processing and in some embodimentsslide processing to process each slide independently.

Embodiments of the invention may further comprise a method of automatedsample processing, comprising the steps of: acquiring or accepting oraccessing information such as protocol or reagent information,transmitting such information to at least one sample processing systemor even a stand alone processing system, and processing samples.Furthermore, embodiments may provide: for handling, maintaining,sharing, and using the sample processing information. These and otheraspects may be provided for individual samples or multiple batchprocessing, and in a real-time manner. It may also be accomplished inand adaptive manner, perhaps for multiple batch processing or the like.

Again, as mentioned, many of the various aspects of the presentinvention are applicable to immunohistochemistry (IHC), as well asin-situ hybridization (ISH) and fluorescent in-situ hybridization(FISH), special staining of samples, microarray processes, andtechniques incorporating target retrieval or the staining of samples,Furthermore, embodiments are directed to processing sequences addressingissues of processing control, and may be particularly applied to slideprocessing systems.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying figures, are incorporated in and form a part of thedescription, illustrate some of the preferred embodiments of the presentinvention. Together with the written description and disclosures of thespecification, they serve to explain principles of the invention and toenable each of the disclosed embodiments.

FIG. 1 is a depiction of an embodiment of an overall systemincorporating some of the features of the invention.

FIG. 2 is a depiction of an embodiment of a portion of a sample carrierassembly of one embodiment of the invention.

FIG. 3 is a depiction of an embodiment of a robotic movement aspect ofone embodiment of the invention.

FIG. 4 is a flow chart of some representative process steps of anembodiment of the invention.

FIG. 5 is a block diagram of an embodiment of the invention.

FIG. 6 is a depiction of an embodiment of a device incorporating some ofthe features of the invention.

FIG. 7 is a depiction of an embodiment connecting one stainer with onemanager & server and one label printer.

FIG. 8 is a depiction of an embodiment connecting multiple stainers withmultiple managers and multiple label printers.

FIG. 9 is a depiction of an embodiment connecting a system to a labnetwork and lab information system.

FIG. 10 is a block diagram showing some of the internal softwarefeatures.

FIG. 11 is a description of representative deparaffinition steps of anembodiment of the invention.

BEST MODES FOR CARRYING OUT THE INVENTION

The following descriptions are provided to describe various embodimentsof the present invention in a manner to facilitate a more detailedunderstanding some of the inventive features. The variously describedexamples and preferred embodiments should not be construed to limit thepresent invention to only the explicitly described systems, techniques,and applications. This description may further be understood toincorporate the various systems, techniques, and applications, bothsingularly and in various combinations consistent with the variousinventive features and embodiments of the present invention.Accordingly, the following is a detailed description of a number ofspecific embodiments of the invention.

FIG. 1 shows one embodiment of a sample processing system 101 inaccordance with the present invention. The sample processing system 101is configured to achieve an appropriate sequence of events that achievesa desired result to some degree. In achieving this sequence in anautomated fashion to some degree the sample processing system is deemedan automated sample processing system and achieves automatic processingof at least one sample. This automated sequence as well as other aspectsof the invention may be controlled by hardware, software, or somecombination of them to accomplish a desired sequence with limited humanintervention. Regardless how achieved, the automated control may beprovided by a process operation control system 171 to direct the variousactivities. As shown in FIG. 10, this (as well as other functionalitiesdiscussed) may be software programming or subroutines; again, it mayalso include hardware or the like. The sample 198 processed may be anymaterial, but is most likely a biologic material such as a biologicalsample or a biological specimen, perhaps such as a histological sample,e.g. tissue and cell specimens, cells, collections of cells, or tissuesamples, the definition to include cell lines, proteins and syntheticpeptides, tissues, cell preps, cell preparations, blood, bodily fluids,bone marrow, cytology specimens, blood smears, thin-layer preparations,and micro arrays. It should also be understood to include slide-basedbiological samples. As used, a sample may be arranged on a carrierelement 197 such as a slide, or microscope slide, or the like that maymaintain the sample's position or integrity. The carrier element 197 maybe configured to move and thus reposition the sample 198. As such, itmay be considered a movable carrier element. In processing a slide, theautomated sample processing system may serve as an automated slideprocessing system.

The automated sequence may involve a significant number of steps. Infact each process can itself require many automated movements to achieveits goal. As but one example, the seemingly simple act of merely placinga stain on a sample or a slide can require a surprising number ofphysical steps. Each of these may involve different valves, motors,switches, relays, or the like. This seemingly simple act can involve:

-   -   beginning X-movement of a robot head;    -   moving the robot head an appropriate distance along an X-axis        for a probe wash location;    -   ending X-movement of the robot head;    -   beginning Y-movement of a robot head;    -   moving the robot head an appropriate distance along an Y-axis        for a probe wash location;    -   ending Y-movement of the robot head;    -   beginning Z-movement of a robot head;    -   lowering a probe tip into a wash area;    -   ending Z-movement of the robot head;    -   switch a valve to activate a probe wash source;    -   open a valve to begin flow of a wash liquid from the probe wash        source;    -   wash the probe;    -   close a valve to end flow of a wash liquid from the probe wash        source;    -   beginning Z-movement of a robot head;    -   raising the probe tip;    -   ending Z-movement of the robot head;    -   beginning X-movement of a robot head;    -   moving a robot head an appropriate distance along an X-axis for        a desired stain container;    -   ending X-movement of the robot head;    -   beginning Y-movement of a robot head;    -   moving a robot head an appropriate distance along an Y-axis for        a desired stain container;    -   ending Y-movement of the robot head;    -   beginning Z-movement of a robot head;    -   lowering the probe tip over a desired stain container;    -   ending Z-movement of the robot head;    -   switch a valve to utilize a stain aspiration pressure source;    -   open a valve to begin access to the stain aspiration pressure        source;    -   aspirate stain;    -   close a valve to end access to the stain aspiration pressure        source;    -   beginning Z-movement of a robot head;    -   raising the stain containing probe tip;    -   ending Z-movement of the robot head;    -   beginning X-movement of a robot head;    -   moving a robot head an appropriate distance along an X-axis for        a particular slide;    -   ending X-movement of the robot head;    -   beginning Y-movement of a robot head;    -   moving a robot head an appropriate distance along an Y-axis for        a particular slide;    -   ending Y-movement of the robot head;    -   beginning Z-movement of a robot head;    -   lowering the stain containing probe tip over a particular slide;    -   ending Z-movement of the robot head;    -   switch a valve to utilize a stain emission pressure source;    -   open a valve to begin access to the stain emission pressure        source;    -   emit stain;    -   close a valve to end access to the stain emission pressure        source;    -   beginning Z-movement of a robot head;    -   raising the empty probe tip; and    -   ending Z-movement of the robot head.        Each of these type of operations or actions may be relevant to        understanding an instrument's operation. Further, each of these        types of operations or even a lesser set of significant events        may be considered important details of the sample process        operation. As explained later, it may be valuable to capture        information relative to a significant number of these actions        such as all of these operations, some subset of these        operations, one-half of these operations, one-third of these        operations, or the like. Further, even the nature or type of the        events that may be if interest may be varies. In general, any        event that may indicate the propriety of operation or processing        may be a subject. Naturally in order to achieve automated        processing it will be necessary to schedule the various sample        process or process operations desired. This can be achieved by        an item of software or the like that acts as a multiple event        scheduler 401.

A particular design of a system may include cabinet sections 102 thatmay form outer portions of the system and serve to address generalstructural considerations of the system (a top cabinet section is notshown in FIG. 1). The sample processing system may also comprise aplurality of drawers 104 used for the handling and processing of samplesand sample carriers such as slides, potentially microscope slides. Othersample carriers may be accommodated consistent with the presentinvention. Each drawer may be configured to accommodate carrierretainment assemblies that hold one or, most likely, a number of theparticular carriers, slides, or samples involved.

In holding slides the carrier retainment assembly serves as a slideretainment assembly 106. There may also be carrier racks, modules, ormagazines encompassed within each of the two broad terms. As oneembodiment of a sample carrier retainment assembly, a slide retainmentassembly 106 is shown in FIG. 2. The slide retainment assembly, andindeed the generic carrier retainment assembly may comprise a sliderack, module, or a number of magazines. The slide retainment assembly106 may be configured to accommodate a plurality of slides in at leastone configuration in corresponding sample carrier retention devices 108.The sample carrier retainment assemblies, are utilized in the processingof samples as further described below. It should be further noted thatthe sample carrier retainment assembly can be removably configured withthe drawers 104, and may be stackable or nested within other retainmentassemblies.

The general sample processing system 101, and even one or more drawers110 in the sample processing system 101 may accommodate processingmaterials such as reagent containers 199 for sample processing, alsofurther described below. A processing material retainment assembly, suchas a container rack 111, shown in FIG. 1, may be utilized to accommodatereagent containers 199 or other processing materials within each ofdrawers 110. Bottle inserts may be preferably configured with theretainment assembly to ensure proper processing material positioningwithin the processing material retainment assembly and the drawer.

Multiple drawers 104 may be included to allow for one or a plurality ofsample processing protocols to be performed by the system 101. Pastefforts at sample processing, as previously described, may have beenlimited to processing sequences for an entire batch of carriers withinthe system. The present invention, however, in part by providing aplurality of drawers and carrier retainment assemblies, may allow forindividual, batch, or multiple batch processing, including real-time oradaptive capabilities, as further described below.

Indicator elements 112 may be provided to indicate a status of thedrawers and the carriers or materials within each drawer for an operatorof the system. In one embodiment, visual indicators, such as lightemitting diodes in preferred embodiments, may be used to indicate if adrawer is available during operation of the sample processing system,and may indicate conditions such as a locked or open condition of acorresponding drawer, carrier capacity status of the drawer or of acarrier retainment assembly within the drawer, and chemical inventorystatus of the sample processing system, such as reagent loading statusor capacity. A warning indication may be given by these or otherindicator elements, as well as other indicative signals. One or aplurality of sensors may be utilized to determine the status of thedrawer as indicated by the indicator elements 112 and to further provideprocessing status as further described below.

A processing material unit may be utilized to provide various processingmaterial to the sample processing system 101 and to afford the hazardousand non-hazardous segregation of waste produced during sample processingand the avoidance of cross-contamination. In one embodiment of thepresent invention, the processing material unit may be configured toaccommodate one or a plurality of containers such as deparaffinizationsolution or other material utilized in sample processing. In someembodiments, the unit may also accommodate waste containers to providefor the collection of waste material from the sample processing. Tubingor other fluid transmission elements may be connected with thecontainers and the sample processing system 101. Tubing or other fluidtransmission elements may also be connected with the waste containersand the system 101.

In accordance with the desire for an automated processing system,embodiments of the present invention may include robotic sample processfunctions or a robotic motion system 172 responsive to the processoperation control system 171 to achieve the desired operation steps.This may further comprise an arm 120 utilized in sample processing,potentially having robotic movement, and in some embodiments, Cartesianmovement. The arm 120 may comprise, in some preferred embodiments, oneor more elements, such as an actuator probe 122, a syringe or probe 124,a sensor element and a non-discrete or other volume fluid and/or airapplicator. The actuator probe may be utilized in the configuration andmanipulation of the carriers in sample processing, further describedbelow. In some preferred embodiments, the actuator probe 122 configuresand manipulates the configuration of slides in the sample carrierretention devices 108 by actuation of carrier adjustment element 130(see for example FIG. 2), and in some embodiments, by contact with theslides. As mentioned, in some embodiments, manipulation or movement ofthe slides or the samples may be accommodated. This movement may resultin a horizontal or vertical configuration of the slides to facilitatesample processing as described below.

As mentioned above, there may be a large number of process stepsaccomplished. As may also be appreciated from the nature of theprocesses envisioned, there may be uses of many different substances orthe like. Whether involving a substance or merely a physical action,these types of items may be considered as relating tooperationally-influential exteriorly-consequential information. The itemmay be operationally-influential in that it either its operation orfailure in operation may directly or indirectly influence some type ofconduct This conduct may be exteriorly-consequential in that it may be aconduct that does not take place within the process system itself butexternal to it. As such the present invention may provide the capabilityto monitor that information. This capability may even be considered asan operationally-influential exteriorly-consequential informationmonitor 402 as shown generally in FIG. 10. Thus the present inventionmay include an ability to monitor information of a broad nature.

As but one example, the present invention may involve monitoringexteriorly-consequential information that is actuallyoperationally-altered outside information in that the activity conductedas part of the process system's operation actually causes a change inthe information. But one example of this might be using up a particularstain substance. By monitoring this category of information, the presentinvention may be considered as monitoring operationally-altered outsideinformation. This embodiment may thus be considered as including anoperationally-altered outside information monitor. Of course, theseevents may be influenced at least in part by at least some of therobotic sample process functions.

As previously mentioned, arm 120 may comprise syringe 124. The syringe124 may be considered a probe in some embodiments, depending upon therequirements of protocols to be performed. Syringe 124 may befluidically connected with and may apply one or more of the following:rinse agents, such as water; containers, potentially removablyfluidically connected for the aspiration of reagents, such as aspirationof reagents from containers and to the samples presented with thecarriers; and blow off or other removal agents such as an air source.Syringe 124 may be utilized to pierce processing material containerssuch as reagent containers. In some embodiments, a reservoir may beprovided with the arm 120 to allow for various volumes to be aspiratedby syringe 124. The unique configuration of the reservoir allows forefficient cleaning and drying of the internal portions of the syringewhile allowing for the accurate pipetting or otherwise aspiration of awide range of volumes.

Arm 120 may, in some preferred embodiments, comprise a sensor element.The sensor element may be used to automatically determine location andother status information of components of the sample processing system,such as reagent containers, or other processing material containers, orsample carriers. This may be used to teach the system proper and/oractual locations, and to calibrate, self-calibrate, or self-align thesystem, or the like.

In preferred embodiments, the sample processing system 101 may includean automatic slide identification element. This may be controlled toachieve the act of automatically identifying said plurality of slides.This may also be more generic such as there may be some type of sensorelement and it may even comprise a reader or scanner, such as a CCDcamera, utilized to determine status information of processingmaterials, such as reagents as well as to identify slides. The sensorelement, for example, may read, detect, or otherwise determineinformation in the sample processing system 101, for example, fromprocessing material containers, such as, for example, reading coded orperhaps encrypted information provided on the container to determinereagent type and reagent location within the system. The sensor elementmay also determine status information of sample carriers. For example,in some embodiments, slides configured with a slide retainment assemblymay be provided with informational indicia, such as a code, that mayindicate information about the sample presented on the slide or theprocessing protocol to be performed. The sensor element may read thecode of the slide to determine the protocol to be performed for theparticular slide and sample.

A cleaning station 140, shown in FIG. 1, may be included to cleanelements of arm 120, and in preferred embodiments, may function to cleanor otherwise remove completely the previously deposited reagent from theprobe, or remove elements containing the internal and/or externalsurface of the probe and/or syringe 124. In one embodiment, the cleaningstation may be configured to clean elements of arm 120, such as syringe124, while such elements are configured with arm 120. The syringe may becleaned, for example, with a water rinse through the syringe while thesyringe is positioned at the cleaning station. In other embodiments ofthe present invention, the cleaning station 140 may be configured toallow a drop off and pick up of elements such as syringes for cleaningwhile allowing the processing throughput of the sample processing systemto continue.

In some embodiments, multiple probes or syringes may be used to applyfluids required for the staining of histological tissues samples mountedor otherwise presented on slides. This may encompass automatic stainingaccomplished through a slide stain element such as the items included onthe robotic motion system 172 discussed above. The sample processingsystem may drop off a “dirty”, contaminated, or used probe or syringeand swap it for a “clean”, uncontaminated, sterilized or an unused one.One or more probes or syringes may be cleaned while the system continuesprocessing of samples, such as applying reagent or stain with analternate probe or syringe.

The system may access, use and wash multiple probes or syringes forpipetting or otherwise aspirating fluids required for the staining ofsamples mounted or otherwise presented on slides. To eliminate crosscontamination, a system with a single reusable probe may wash the probebetween each fluid applied. The task of washing the probe can have alarge impact on the throughput of the overall system. The presentinvention may allow for multiple probes to be available to the systemfor use. The system may continuously have a clean, uncontaminated,sterilized, or an unused probe available to use and sample processing isnot impacted by the required cleaning routine. The cleaning routine maybe necessary to eliminate the possible cross contamination of fluidsand, in some embodiments, may take up to about 1 minute to accomplish.The cumulative impact of the cleaning routine on a series of processingsteps can add time to the throughput capabilities of the system. Theaddition of multiple probes or syringes may eliminate this impact andsignificantly decreases the time required to process the samples.

Embodiments of the present invention may comprise a mixing station 150,shown in FIG. 1. The system may mix component fluids, such as dyes,buffers, or other processing materials, preferably on demand and as theprocessing steps and protocols dictate. Fluids required during theprocessing steps may sometimes need to be mixed with other fluids tocreate a final activated fluid mixture or cocktail. However, theactivity levels of these mixtures can be time sensitive and maytherefore only be effective for a short period of time. The on demandmixing of fluids is advantageous in that it allows the fluids to bemixed immediately before being used. The syringe or probe 124, inpreferred embodiments, will aspirate fluids into and from the mixingstation 150 to mix component fluids. A rinse may further be dispensedinto the mixing station to sterilize the station.

In preferred embodiments, slides are movable and configurable in bothvertical and horizontal positions as required for the pretreatment andstaining process. This allows for the automation of the pretreatment andstaining of slides in various manners, including pretreatment andstaining as accepted in conventional manual laboratory methods. Theslides are initially loaded into the carrier retention assemblies, suchas slide racks, and drawers in the horizontal position. If pretreatmentis required, such as deparaffinization, the system rotates the slideinto the vertical position and lowers these samples into a processingtank, further described below, filled with the required fluids. In someembodiments, the slide rack is lowered to affect lowering of the slides(see FIG. 2). To perform the staining process on the slides, asdescribed below, the System rotates or moves the slide to the horizontalposition and a syringe or probe applies fluid to the sample, providing ahorizontal staining of the sample. Each slide can be rotatedindependently allowing for the independent processing of differentsamples with different requirements.

The system automates, and in some embodiments mimics or otherwisecorresponds to the procedure and physical attributes of the suppliesused manually to perform these same pre-treatment processes.Accordingly, a processing tank may be provided. In some embodiments,components of each processing tank may be configured within a drawer104. In some preferred embodiments, the fluids volume needed to performpre-treatment processes are maintained but instead of the slideorientation with each other being face-to-face, as in conventionalsystems, they are side-to-side, although other slide configurations arenot disclaimed. The processing tanks provide even distribution of fluidsacross the face of the slide.

In some embodiments, the processing tanks have the ability to heat andcool the slides. Heat may also be applied to each individual slide by athermal device. The precision and physical application of thetemperature control can result in standardization and repeatability ofprocess steps. Filling and heating tasks are performed by a computercontrolled scheduler, as further described below. Fluid volume may beadjusted to account for the presence or absence of any number of slides.

In some embodiments, the individual fluids used for pretreatment may becontained in the system cabinet. Deparaffinization fluids (except DIwater) may be drawn into the processing tanks, then returned to theircontainers for reuse. Containers are as listed for fluids one throughsix. On a periodic basis, the material in the “dirty” containers may bediscarded. The “clean” containers may be moved up to the dirty position,and then fresh fluid added to clean position. DI water may be drawn fromthe large system DI water container, and discarded after each use.Target retrieval solution may be drawn from dedicated containers, andmay be recycled or discarded after each use.

Returning to the aspect of monitoring or capturing information, anembodiment of the system may be designed to monitor replenishable supplyinformation, such as the status of buffers, reagents, stains or thelike. By monitoring for a potential need for replenishable supplies thesystem may not only provide the replenishable supply information monitor403 shown in FIG. 10, but it may also relieve operators of someconcerns. It may also remove at least one possibility for human error.Significantly, the system may also act to automatically notify anynumber of people relative to the information monitored. With respect toreplenishable supply information, the system may notify a user, anoperator, an administrator, or even a supplier of an actual, potential,or impending need to replenish supplies. As such the system may beconsidered as including an automatic notice element 404, or an automaticoperator replenishable supply notice element, an automatic supplierreplenishable supply notice element, or the like.

In a similar fashion, an embodiment of the system may monitor or captureinformation that is of interest to the continued or continuous operationof the device. As such it may be monitoring instrument maintenanceinformation. This may include, but is not limited to monitoring partcycle information, ranging from a gross information such as age of thedevice, estimated number of cycles, to even monitoring specificinformation such as monitoring individual part cycle information (e.g.,how many times and actual valve was turned on or off, etc). By includingan instrument maintenance monitor, an instrument maintenance informationmonitor 405, a part cycle monitor, or an individual part cycle monitor406, the system may facilitate not only enhanced reliability andcontinuous operation, but it may permit preventative maintenance such asmaintenance based on product cycles or mean times between failures.Naturally, it may also use the automatic notice element 404 such asproviding an automatic maintenance notice element to inform a wide rangeof persons of such issues.

Of course, a large variety of information may be monitored; embodimentsof the system may monitor or capture information that relates tomaterial requirements, such as expiration dates, lot information or thelike. Thus the present invention may include a material requirementinformation monitor 407 so that it acts to automatically monitormaterial requirement information. This may be a product expirationinformation monitor 408 that may even act with respect to an upcomingexpiration and may even cause the set of automatically advance notifyinga person by providing an automatic advance expiration notice element.For items that may be very important there may even be multiple noticeseither concurrently or sequentially and as such the system may include amultiple advance expiration notice element. Another type of informationthat may be monitored is historical usage information such asinformation of a statistical or past nature. Thus the system may includean historical usage information monitor 409. From this, predictiveestimates may even be made such as a likely date upon which to order anitem or the like. Through monitoring predictive usage information, thismay be one way the system may be able to provide an automatic predictiveneed notice element or even a predictive usage information element 410.It may also provide for a user statistical information monitor so thatit can assemble and monitoring user statistical information and act onthis such as by comparing to other historical or statistical informationor the like. The present invention may also be configured to monitorsample process efficacy information such as by assuring particularprotocols are followed or the like and may thus provide a processefficacy information monitor 411. Monitored information may beextrapolated to permit a totalizator 413 capability by adding upindividual usages to know amounts left or otherwise impacted byoperation. This may include totalizing usage information for an itemsuch as a reagent or an individual part's cycles. Such a capability mayserve as a totalization usage information monitor, a reagenttotalizator, or a part cycle totalizator. By having a data captureelement 414, the system may generate data that may include or permitanalysis or use of a variety of aspects, including but not limited to:number of occurrence data, part operation data, amount of usage data,and amount of material used data. Such data may, of course, have a likeelement, perhaps a subroutine, to do or generate the various function ordata involved.

In some embodiments, an imaging device such as an image-capture 2-Doptical sensor, perhaps a CCD camera, or the like, may be used todetermine the position of the sample on the slide, providing for greateraccuracy during sample processing. Embodiments of the sample processingsystem 101 may further provide sample diagnostic capabilities.Accordingly, in some embodiments, a device may analyze samples. A cameramay be used for diagnostic purposes. In some embodiments, the sample maybe scanned for further analysis, potentially by computer. The camera canalso be used 1) as an area locator, 2) to locate a tissue area, 3) toapply reagent based on location and area. The scanned image may beanalyzed for reagent analysis or other analyses.

The system may also generate or also monitor subject sample data.Relative to the imaging device, the system may monitor or perhapscapture image data, such a sample image data, substance image data,system image data, and even pre- and post-event image data. Each ofthese may be systematically stored for some purpose. Each of these maycorrespondingly be considered to present an appropriate element such asa system image data capture element, a substance image data captureelement, a sample image data capture element, and a pre- and post-eventimage data capture element. In addition, there may be included amultiple image data capture element so that more than one image mayexist to prove or evidence an aspect of the processing. Again, thesystem may act to systematically store and one or the multiple images socreated. Collections of like data, such as groupings of individualsample process data, individual slide log data, and even type ofprotocol data may also be created.

The processing of samples may be accomplished according to somepreferred embodiments as shown in FIG. 4 and FIG. 11 consistent withfeatures of the present invention. Variants of these protocols andprocessing steps, or other processing steps, may be accomplishedconsistent with the present invention.

One processing sequence may broadly comprise the pre-processing of asample, if needed, such as deparaffinization (as previously described),and further comprise target or epitope retrieval (as previouslydescribed), and sample staining.

In some embodiments, specifics of in-situ hybridization (ISH) may beaddressed. Embodiments of ISH may require a small volume of reagent,such as 15 microliters, to be placed on the sample. Heat control may bemaintained between about 95-100 C and kept constant for a period oftime. Temperature may then be lowered in a controlled manner.

Furthermore, fluorescent staining or tagging in IHC or ISH (FISH) may beperformed consistent with the features of the present invention.

As mentioned, the sample processing system may automate the processingof samples mounted on carriers or slides. This configuration of thesystem allows for the flexibility for both continuous, individual, andbatch processing of slides with the design lending itself to meetestablished laboratory workflow demands. The multiple independent andredundant slide processing subsystems found within the system may alsomaintain its ability to process each slide independently.

The automatic processing may be achieved by designing a system withautomated process operation capability or sequencing through at leastsome steps without human intervention that may be controlled by or actin response to a process operation control system 171. This may beprovided through hardware, software, or some combination of the two. Oneconceptual embodiment depicts some of the various capabilities in FIG.10. Of course, the user needs the ability to specify the nature andsequence of the various steps or acts desired. This can be accomplishedby an input parameter capability 173 through the inclusion of even asample process parameter input 173. This input can be retained by thecreation of stored parameter process data 174. In order to facilitateuninterrupted processing, the input parameter capability 173 may beconfigured as an independent process parameter input with respect to theprocess operation control system 171, such that acts caused by theprocess operation control system 171 are unaffected by any action withrespect to the independent process parameter input. Further, the inputparameter capability 173 may also be configured as an autonomous inputfunctionality through the inclusion of an autonomous input element.

Capabilities may not only act independent of the automated processoperation capabilities, but they may be fully functional even withoutthe presence or operability of the automated process operationcapability (which itself may or may not be in a process device). Thismay be achieved in a variety of manners, including by providing aseparate full function computer 181 (e.g., separate from the capabilityprovided or required by a process system) or that may be programmed toaccomplish the input. In addition, in order to accomplish a goal ofaddressing practical and institutional needs, any capability may beconfigured to provide simplified use and may even be available in ahighly simplified level of detail. This may be a “wizard” type of systemwhere there is a “step-by-step” method for functions such as programmingslides, adding slides, achieving the desired input, or the like. Such anaspect may even be simple, regimented, and somewhat inflexible. Astructured or simplified input can facilitate input by persons notrequired to have the full spectrum of skills necessary to be responsiblefor the operation of the sample processing system 101.

As part of the functions of monitoring or perhaps allowing play back ofevents, the system may include some type of data capture element 414. Asmay be appreciated from the initial discussion of the types of actionspotentially needing to be programmed, the data capture element 414 maycapture individual movement data, only robotic action data, individualrobotic movement data, individual operation data, or even individualusage data. Thus the data capture element 414 may be an individualmovement data capture element, a robotic action data capture element, anindividual robotic movement data capture element, or an individualoperation data capture element. All or any part of this data may besystematically stored such as storing all important details, onlyparticularly important details (e.g., relative to highly sensitivevalves, substances, or the like) or even only a significant number ofdetails relative to sample process operations. Thus the data captureelement 414 may be a systematic process detail capture element. Oncecaptured, this data may be stored in a number of fashions. There may bea memory location at which such data resides and this may thus representa significant process detail memory 412. It may also represent a subjectsample data capture element and any of the memory types mentionedearlier may be used for such a purpose.

In storing the data, the system may create a segmented computer file,that is a file that contains only such data so that it is not asmanipulatable as other files. This may aid in assuring the accuracy oreven certifiability of the events depicted. For instance for anyparticular sample, there may be automatically generated upon request asimulation—perhaps with a time base appended—of what happened to thatparticular sample as well as pictures of the sample before and after itsprocessing. The data so stored may even be created as an inalterablecomputer record and perhaps may even include an integral change indiciathat can prove its accuracy. When stored, the system may create a commonformat computer record so that user can easily work with it or it maycreate a proprietary format computer record that cannot be altered orthe like. Thus the significant process detail memory 412 may represent asegmented computer file memory element, an inalterable computer recordmemory element, an integral change indicia memory element, a commonformat computer record memory element, or a proprietary format computerrecord memory element.

The capture of data may include time of occurrence data, such as actualdate data, actual time data (e.g., UTC, etc.), precise time data (e.g.,hours, minutes, seconds), relative time data, absolute time data,initiation time data, and even completion time data (e.g., process,protocol, motor operation events, or the like). Again, the data captureelement 414 may include, but is not limited to, a time of occurrencedata capture element, an actual date data capture element, an actualtime data capture element, a precise time data capture element, arelative time data capture element, an absolute time data captureelement, an initiation time data capture element, or a completion timedata capture element.

One item that may be of particular user desire is the fact that the datacapture element 414 may represent an individual sample process datacapture element, an individual slide log data capture element, a type ofprotocol data capture element, and even an individual slide log datacapture element. There may also be a real time individual slide log datadisplay to show actual processing as it occurs.

As used above, the slide identification information may represent anyinformation unique to a particular slide, such as a serial number,patient number, patient name, unique image, or the like. In keeping withprivacy concerns, there may also be coded or perhaps encryptedidentification information or internal identification information thatothers cannot use to identify the particular patient involved or thelike. As discussed below and as shown in FIGS. 8 & 9, the overall systemmay include a number of staining instruments and thus the input caninclude preferred stainer information (which may or may not be indicatedor accepted by the automated system). Provision can also be included toachieve a rush test and as such there may be an immediate, urgent, orotherwise known as stat (an often used medical term for immediate)process request information element. Such may also be linked with userprivileges information so that only certain individuals may displaceother tests to create a different priority. Of course all permutationsand combinations of the above may be included.

For automated operation, the input may create data such as parameterprocess data 174 that may be stored at some location. To provideautonomous operation, it may be independently stored perhaps in aphysically independent memory even at a location remote from an actualstainer itself. This may be accomplished by utilizing a primary orsecondary storage perhaps of a separate full function computerprogrammed or configured to accept and/or store data. In such a fashion,the computer may contain what could be considered as an independentprocess parameter memory 174. Since the computer is likely physicallyseparate, it may be considered to have a physically independent memoryperhaps even a remote location memory if it is remote from the processequipment

By using independent memory and independent other functionality, thesystem may facilitate full operational functionality of the automatedprocess operation capability. Since the automated process operationcapability is fully operational during operation of either the memory orinput, the storing or inputting or other function can be conductedwithout interrupting the process operation. Thus the inputs can be lateraccessed at a process time independent of the time of accomplishingslide process parameter input or storing. In addition, entry or storingmay also be accomplished at least in part concurrently with theprocessing of certain samples. This processing may even be initiatedsignificantly after completion of the slide process parameter inputaction. Such may occur at least about one hour after the input, at leastabout three hours after the input, at least about eight hours after theinput, at least about one day after the input, at least about two daysafter the input, and at least about one week after the input.

As mentioned briefly above, once the information is either monitored orcaptured, the present invention may act to automatically inform at leastone person who may find the information useful. The automatic noticeelement 404 mentioned earlier may be configured to act as an automaticexteriorly-consequential information notice element by relating largelyto that type of information. Of course, the automatic notice element 404may act in response to the step of monitoring the particular informationinvolved. For example, if it is monitoring operationally-altered outsideinformation, the automatic notice element 404 may act as an automaticoperationally-altered outside information notice element. For processevents that are merely captured and not automatically monitored, aperson may prompt the system upon which it may provide information bysome type of display 415. This display (in its broadest sense) mayreveal at least some information, perhaps relative to sample processoperations to at least one person. If the display reveals significantprocess detail information, it may be considered as a significantprocess detail information display. Further if it displays at a separatelocation there may even be a significant process data transfer elementto facilitate remotely displaying such information. As such the display415 may be considered a remote process detail information display. Asmentioned earlier, the system may provide for a real time informationdisplay, that is a display that reveals information at about the time itoccurs. By real time displaying information remotely, the operator orany other interested person may be able to “watch” or monitor theprogress of the instrument from another location—perhaps even the otherside of the world. This may be particularly valuable when there is areal time display of individual slide log data as mentioned above.

One type of display 415 that may be noteworthy is the fact thatembodiments of the invention may create a simulated motion display. Thesimulation may visually show an element moving on a screen just as therobot head actually moved when it operated. Embodiments can providesequential playback capability so that one could also “watch” theinstrument just at it operated at some earlier time. There may also bean altered speed sequential playback capability, a user alterable speedsequential playback capability, or merely a high speed sequentialplayback capability perhaps all with or without pause or slow motioncapability. With this capability, the display 415 may represent asimulated motion process detail information display. The system may thusinclude a sequential playback element, an altered speed sequentialplayback element, a user alterable speed sequential playback element,and a high speed sequential playback element.

All this information must, of course be used by some person. Anyinterested person may have the information available to them, such as anoperator (e.g., anyone responsible for all or a portion of a process orthe instrument), an instrument operator (e.g., an individual physicallyresponsible for all or a portion of a process), an administrator (e.g.,a person managing operators or perhaps responsible for order placement),a substance or other supplier, or even a manufacturer, such as forsupport and maintenance capability. For events that may require externalactions (e.g., ordering more reagent or the like), the system mayautomatically notify at least one of these types of people and thus theautomatic notice element 404 may be considered as representing anautomatic operator notice element, an automatic administrator noticeelement, an automatic supplier notice element, or an automaticmanufacturer notice element. It may also be considered as representingan automatic operator exteriorly-consequential information noticeelement, an automatic administrator exteriorly-consequential informationnotice element, an automatic supplier exteriorly-consequentialinformation notice element, or an automatic manufacturerexteriorly-consequential information notice element.

Notice may be given at a variety of times. The system may act toautomatically advance notify a person such as of an upcoming expirationdate or of a need to reorder in advance. In so doing it may have or haveinput to it some type of lead time information that tells it how earlyto take the action. By properly configuring a lead time information dataelement 416, lead time may vary by location and situation, for example amachine around the world or used continuously for critical processingmay have a longer lead time than a machine right next to a supplier orused only sporadically. Order lead time information, reagent order leadtime information, maintenance lead time information (any of which mayvary over the course of a year or from time to time) may be utilized andas such the lead time information data element 416 may represent anorder lead time information data element, a reagent order lead timeinformation data element, or a maintenance lead time information dataelement.

Notice itself may be displayed in a variety of ways. The system mayautomatically E-mail a person through inclusion of an E-mail noticeelement; it may automatically print out (including faxing) a notice byhaving an automatic printout notice element. Among other possibilities,it may automatically utilize a telephone line for simulated orreproduced voice or other information by having an automatic telephoneline utilization element.

The actual event of providing notice may be automatic or it may bycaused by some type of user prompt 417. By accepting a monitoredinformation user prompt the system may represent a monitored informationuser prompt. The prompt itself may be a mere software selection or evena mere click-on items such as a software displayed button or the like.Whether displayed and acted upon remotely or at the actualrobot-containing housing, such a user prompt 417 may cause a remoteaccess connection to be established and as a result at least somesignificant process data may be displayed. In such a manner the userprompt may represent an information access prompt element, a softwareselection element, or a remote access element.

In some embodiments, the system may be comprised of independent orperhaps redundant slide staining modules (some embodiments may compriseeight modules) as shown for some embodiments in FIGS. 1 and 6.Throughput may be based on the time to first result with the systemallowing access to completed slides as soon as a staining module hascompleted the scheduled staining tasks. The multiple independent orredundant staining modules may allow for both continuous and batchprocessing of slides. Additionally, each independent staining module mayalso allow for the independent pre-treatment and staining of each slide.A carrier retainment assembly, such as a slide retainment assembly, maybe used to introduce slides to be processed into the drawer 104, thedrawer, slide retainment assembly, and components thereof forming astain module. The slides may occupy one or more positions of the slideretainment assembly, such as at carrier retention devices, up to thecapacity of the slide retainment assembly with the potential for eachslide being processed independently of other slides configured with theslide rack. Embodiments of the stain modules, drawers, slide racks, andcomponents thereof are also shown in FIG. 6. FIG. 6 also provides otherembodiments of system features, such as an embodiment of the arm 120 andthe component features of the arm.

Slide retainment assemblies having one or more slides and even reagentcontainers may be introduced into the staining or reagent modules byintroduction into drawers 104 one at a time or in any combination untilall or an appropriate number of staining modules are appropriatelyoccupied. There may be no restrictions as to the order, number or timingof when the slide retainment assemblies are introduced into the system,the system may also allow for adaptive scheduling of sample loading.Staining modules, and in some embodiments the drawers of the stainingmodules, may lock out access to the slides during the processing periodand may release them to the operator upon completion of the staining orother process on the last slide of that module. In some embodiments, theorder in which the slide retainment assemblies are released may bedependant on the time required to process the last slide of theretainment assembly. Slides may even be processed in the most timeefficient manner independently of the order to which they wereintroduced into the system. The system may provide an optimum or merelyan enhanced temporal scheduling of the various sample process steps. Toaccomplish this, the system may automatically schedule steps that areinterspersed for an enhanced time result. This interspersing may be aninterleaving of a number of process operations and even an interleavingof a number of individual sample operations. In addition to interleavingsteps, the system may sequence the individual sample operations.Regardless as to how programmed, it may be configured through hardwareor software or a combination of each to provide an enhanced temporalscheduler element 179, a process operations interleave element, anindividual sample operations interleave element, or even an individualsample operations sequence element. These can be created by integratingthe automated process operation capability and either the parameter dataor perhaps some replicated portion of that parameter process data (asmentioned later) and can thus act to create an interspersial roboticcontrol functionality 175.

The control of the processing samples may be accomplished according tothe following preferred embodiments, one preferred embodiment shown inFIG. 5, although other processing may be accomplished consistent withthe present invention.

As shown in FIGS. 8 & 9, in expanded systems, a sample processing systemmanager, such as a computer server may be connected with a number ofindividual sample processing systems. These may represent automatedslide stainers or even stand alone automated slide processing systemsuch that they are fully capable of functioning with connection to otherdevices. In systems where a connection does exist, the capability ofelectronically connecting a number of automated slide stainers orautomated sample processing systems or label printers 200, may beprovided. As mentioned earlier, there may be one or more separate fullfunction computers connected. These may be connected through a hub 193.There may be a multitasked central processing unit resource on eitherthe stainer or the computer or there may be a number of of centralprocessing units that are configured to avoid using or implementing amultitasked central processing unit resource relative to the processoperations in order to maintain full independence or perhaps evenautonomous operation. The connection, whether for input or otheroperation may also be a remote link (including ability to be made remotesuch as in detachable memory) such as an internet connection element, atelephone line connection element, a wireless communication element, oreven a detachable memory element. In a preferred embodiment, connectionamong perhaps a number of process systems and perhaps a number ofcomputers, such as workstations and a server (the latter residing eitherseparately or as part of a workstation), may be achieved by use of alocal area network (LAN), such as a group of computers and associateddevices that share a common communications line or perhaps wireless linkand may even share the resources of a single processor, memory, orserver within a small geographic area (for example, within an officebuilding or complex). A local area network for this type of system mayalso include features such as but not limited to: an Ethernet element, atoken ring element, an arcnet element, a fiber distributed datainterface element, an industry specification protocol, a bluetooth-basedelement (named but not contemporary to King Harald Bluetooth of Denmarkin the mid-tenth century!), a telecommunications industry specificationusing a frequency band of 2.45 GHz, a communication specificationapplying an IEEE 802 standard, a frequency hop communicationspecification, a shared common link element, a transmission controlprotocol/internet protocol communication element, a packetizedinformation protocol, a shared protocol, a proprietary protocol, andeven a layered protocol exchange system. By providing an electronicconnection 176 between various resources, the local area network such asthe stainer network 183 (a network dedicated to only the stainer orperhaps sample processing resources for integrity, security, and otherpurposes) in one embodiment may transmit a electronic memory address toachieve access to the appropriate information. Connection may also beestablished to a lab network, facilities intranet system, or even a labinformation system 195 such as through a bridge 194.

As mentioned, connection may be accomplished over internet connectionsbut more preferably is accomplished over local area network connections.Each sample processing system may be individually controlled, in someembodiments, by a PC attached with, internal to, or otherwise provided.Data sharing between sample processing systems and the system managermay be performed to allow identification, tracking, and status of samplebatches, reagents, and other agents and components of the sampleprocessing system. A determination of which system has which reagents,reagent type, slides and protocols may be performed. Log files for eachprocessing sequence, protocol, or slide can be generated for monitoringprocessing status. Database maintenance (including but not limited topurge, compact, back-up, database/list functions) and system diagnostics(including but not limited to exercising active system components toverify proper operation and assisting in troubleshooting efforts) may beaccomplished manually or automatically.

The system may be configured to automatically access the required datathrough operation of the process operation control system 171 byinclusion of an automatic memory access element This access may beachieved by specifying an electronic memory address that may betransmitted by a electronic memory address element 178 perhaps over alocal area network and may be followed by automatically replicating thatdata on some a memory aspect appropriate for operation such as anautomatic data replication memory. This memory may include but not belimited to: a volatile memory functionality as implemented by a volatilememory element, a random access memory functionality as implemented by arandom access memory element, a non-volatile memory functionality asimplemented by a a non-volatile memory element, an electrically erasableprogrammable read only memory functionality as implemented by anelectrically erasable programmable read only memory element, a mainstorage functionality as implemented by a main storage element, asecondary storage functionality as implemented by a secondary storageelement, a cache memory functionality as implemented by a cache memoryelement, and even a detachable memory functionality as implemented by adetachable memory element

A control interface may be provided for the operator, such as agraphical user interface (GUI), and may accommodate various languages.Help menus may be provided to assist in sample processing. Passwordprotection features can be provided and even administrator control overat least some aspects. This may include the capability to includeadministrator limitations on the functional availability of any aspectof the system or of specific stainer availability or functionality,certain reagent availability functionality, certain protocolavailability functionality, patient identification information accessfunctionality, process priority request functionality, and immediate,urgent, or stat process request functionality. By including anadministrator control element 180, the system may have anadministrator-implemented user limitation element, a specific staineravailability limitation element, a certain reagent availabilitylimitation element, a certain protocol availability limitation element,a patient identification information access limitation element, aprocess priority request limitation element, an immediate, urgent, orperhaps stat process request limitation element, a user privileges inputelement, and even a user group privileges configuration or inputelement.

Control of the sample processing may be accomplished by a dynamicscheduling algorithm, and in some embodiments, in accordance withcontinuous, or batch processing previously described. The processingsequence may be controlled, in preferred embodiments, such that thevarious steps of a protocol for samples may be automated by one or morealgorithmic controls. As part of input to establish the desired controlfunctionality, user or other input may be accommodated as follows: 1)selecting a first protocol step, 2) selecting a second protocol from arestricted list of menu items that are compatible with the firstprotocol step, and 3) selecting subsequent protocol steps from arestricted list of menu items that are compatible with the precedingprotocol step.

After all data is input, the system may act to determine operationalreadiness by inclusion of an operational readiness determination element177 that may be programmed to assess if appropriate resources, drawers,slides, reagents, or other aspects are present or available to thesystem. Once an appropriate operational readiness is determined, thesystem may prompt initiation of access of the input data toelectronically determine operational availability of a variety of items.These may include but are not limited to: an individual sample elementthrough inclusion of an individual sample readiness determinationelement, a defined group of samples through inclusion of a defined groupof samples readiness determination element, a physically groupedcollection of samples through inclusion of a physically groupedcollection of samples readiness determination element, a slide drawercomponent through inclusion of a slide drawer component readinessdetermination element, a stand alone automated slide processing systemthrough inclusion of an stand alone automated slide processing systemreadiness determination element, a slide stainer system element throughinclusion of a slide stainer system readiness determination element, andeven a user initiated prompt signal such as might occur to force oractivate the system manually by the inclusion of a user initiated promptsignal determination element.

There may even be timing tolerances, referred to in some embodiments as“bubble tolerance”, that may be controlled as between steps, such asbetween aspiration cycles. Additional control may be accomplishedthrough timing algorithms to determine time tolerances of components ofthe processing system, such as the monitoring of “shelf life” orviability of reagents. Furthermore, adaptive scheduling of sample andslide insertion and removal into the system, as previously described,may be accommodated on an on-going basis throughout operation of thesample processing system.

One aspect of the invention focuses on an automated staining apparatusand a method of automated treating of samples. As to this aspect, thepresent invention relates to an automated staining apparatus fortreating samples arranged on carrier elements or means, such as but notlimited to microscope slides, located at defined positions close to orin the apparatus by removing a portion of selected reagent from astation containing a plurality of reagents and thereafter applying thereagent to a sample, e.g. a tissue, organic cells, bacteria etc.,arranged on the carrier means. This aspect of the invention facilitatesthat two or more reagents are mixed and the mixture applied to a sample.It also relates to a method of automated treating of samples by mixingreagents and applying the mixture to the samples.

Staining apparatuses for staining and treating samples by means of aprobe normally comprises a first station for containing one or morereagent vials; a second station for mounting slides, a probe arrangedfor removing a portion of reagent from a selected reagent vial andapplying the reagent to a slide on which the sample is arranged and adrive means for moving the probe between the various stations.

An object of this aspect of the present invention is to improve theknown apparatuses for staining samples as well as the method forautomatic staining of samples by facilitating a wider range of availableprocesses or procedures used to implement treatment, so as to ease theimplementation of different staining and/or treatment processes that maybe performed automatically, alternatively or additionally to provide anincreased quality of some specific staining processes.

The term staining is used for the end product of the process, by whichcertain parts of the sample may be stained, i.e. has obtained adifferent colour, either in the optic range or in anotherelectromagnetic range, such as ultra violet, or the staining may be andetectable, preferably automatically detectable, change in properties,such as fluorescent properties, magnetic properties, electricalproperties or radioactive properties. To obtain the staining, the samplenormally has to undergo a series of treatment steps, such as washing,binding of reagents to the specific parts of the sample, activation ofthe reagents, etc. and each treatment step may include a plurality ofindividual treatments.

In some staining processes, it may be required for one or moretreatments to use a mixture of reagents prepared from two or moreseparate reagents which may be somewhat incompatible e.g. unmixable,such as a water based and an oil based reagent, or insoluble, andtherefore requires that the two or more reagents are manually preparedand introduced into a reagent vial shortly before starting the stainingprocess in order to obtain the best possible staining result for theselected examination purposes. For other processes, different stainingprocess steps require a mixture of the same two reagents but indifferent dissolved ratios. Some process steps require mixtures of twoor more reagents that, when mixed, have a limited time window ofusability because internal chemical processes deteriorate the mixture.By providing a staining apparatus having an automated mixer integratedtherein, these types of staining processes can be performedautomatically instead of requiring human interaction or manualperformance of some process steps in a much more automated process, andthe quality of the staining process may be improved as a desired degreeof mixing of reagents may be provided or an optimal application timewindow for a deteriorating mixture may be reached.

The carrier elements or perhaps means are preferably arranged in groupsor series on trays or the like, so that a plurality of carrier means maybe removed from or situated in the apparatus simultaneously, and theapparatus preferably also comprises means for performing theintermediate storage of the carrier means with samples thereon and theremoval of the carrier means from the apparatus automatically.

The operation of the staining apparatus may generally be controlled bymeans of a control element or perhaps a control means, typically acomputer having a central processing unit and one or more memory unitsassociated therewith, an control element or perhaps a means forcontrolling the various operations of the apparatus by controllingstepper motors, solenoids, valves and/or other drive or control parts ofthe apparatus. The control means may have one or more data communicationports for enabling data communication with external computers by wire orwireless. The control means does not have to be physically arrangedwithin the apparatus itself but may be a computer external to thestaining apparatus and connected to the apparatus via a datatransmission port thereof.

The operation of the staining apparatus will generally be controlled bymeans of control means, typically a computer having a central processingunit and one or more memory unit associated therewith, means forcontrolling the various operations of the apparatus by controllingstepper motors, solenoids, valves and/or other drive or control parts ofthe apparatus. The control means may have one or more data communicationports for enabling data communication with external computers by wire orwireless elements. The control element or perhaps means does not have tobe physically arranged within the apparatus itself but may be a computerexternal to the staining apparatus and connected to the apparatus via adata transmission port thereof.

The present invention also relates to a method of fully automatedtreating of samples arranged on carrier elements by means of a stainingapparatus controlled by means of a control element or means, wherein themethod comprises the steps of situating a plurality of carrier meansintermediately in a carrier means station, each carrier means having asample arranged thereon, applying a portion of a first reagent selectedfrom a plurality of reagents to a mixing cup, applying a portion of asecond reagent selected from a plurality of reagents to the mixing cup,mixing the reagents in the mixing cup by means of mixing means, moving aprobe to the mixing cup by means of a probe drive means, removing aportion of the mixed reagents from the mixing cup by means of the probe,moving the probe to a selected one of said carrier means, and applyingthe mixed reagents to the selected carrier means, so as to perform atreatment of the sample arranged on the selected carrier means.

The present invention further relates to the use of an apparatus of thepresent invention as described above for exercising the method of thepresent invention.

The embodiment shown in the figures and described in details below isonly an example of an apparatus in accordance with the present inventionand is not limiting the wider scope of the invention as described in theenclosed claims.

As shown in FIG. 6, a detailed description of one embodiment of thisaspect of the invention involves staining apparatus 201. The stainingapparatus 201 may comprise a rectangular frame 204 surrounding a firststation 202 comprising an array of compartments wherein each compartmenta reagent vial 203 is placed, and a second station 205 wherein a numberof separate racks 206 is placed, and where each rack may comprise anumber of slides 207 mounted side by side in the rack 206. In theembodiment shown, each rack may hold up to 17 slides, but the rack maybe designed to hold any suitable number of slides. With eight racksarranged side by side, the shown embodiments may hold up to 136 slides207 each having a sample, e.g. a tissue mounted on the upper side of theslide, so that reagent may be applied from above to the sample on eachslide.

A robot arm to move a probe 210 in X and Y direction as indicated by thearrows X and Y may be arranged above the frame 204 of the stainingapparatus. The robot arm may therefore position the probe 210 above allreagent containers 203 as well as above all the slides 207, and mayfurther operate the probe 210 to remove portions of a reagent containedin any of the containers 203, to transfer the portion of reagent andapply it to any of the slides 207 in order to provide a selectedstaining or treatment of the sample on each slide 207. By use of asuitable control element, e.g. a computer having the appropriatesoftware, subroutines, or input data for the purpose, this stainingapparatus 201 may be able to automatically stain or treat samplesrequiring different staining or treatment reagents and processes.

Having the appropriate input data, the control element or perhaps meansof the apparatus may operate the robot arm to commence a staining ortreatment run by moving the probe to a first reagent container 203, intowhich the probe tip is inserted and liquid is aspirated up into theprobe 210 in an amount corresponding to the number of samples to bestained or treated, in accordance with the input data provided to thecontrol element. Additionally, under certain conditions, the instrumentmay be required to perform a reagent inventory before a staining ortreatment run can commence. This inventory may be accomplished by use ofthe probe tip to actually touch the liquid surface in each reagent vial203. To prevent cross-contamination between the reagents in the variouscontainers 203, a cleaning of the probe 210 or at least the probe tipmay be required after each measurement of a reagent level.

The probe 210 may be moved by the robot arm towards the slide retainmentassembly 205 in which the slides 207 are mounted. The slides 207 may besituated with the surface horizontally oriented and the probe 124 maydispense the required amount of reagent on the appropriate slides inaccordance with the input data. Alternatively, the probe 124 may bemoved by the robot arm towards the reagent mixer 209 where it mayrelease reagent into the cup of the reagent mixer 209, and may besubsequently moved to the probe washing station 208. The robot arm maymove the new clean probe to a second selected reagent vial 203 forcollecting a selected amount of reagent from the second vial 203, andthe probe may thereafter by means of the robot arm be moved to thereagent mixer 209, where the reagent in the probe 210 may be releasedinto the cup of the mixer containing the first selected reagent. Thismay be commenced several times if more than two reagents are to be mixedfor a specific staining or treatment process.

An object of the present invention is to provide a staining apparatusand a method for automatic staining of samples, in which the totalprocess time for completing or even entering the staining protocol maybe reduced. In particular, it is an object of this aspect of theinvention to reduce the amount of time needed in general.

As can be easily understood from the foregoing, the basic concepts ofthe present invention may be embodied in a variety of ways. It involvesboth sample processing techniques as well as various systems,assemblies, and devices to accomplish sample processing, input, andother functions. In this application, the sample processing techniquesare also disclosed as part of the results shown to be achieved by thevarious systems, assemblies, and devices described and as steps whichare inherent to utilization. They should be understood to be the naturalresult of utilizing the devices as intended and described. In addition,while some devices are disclosed, it should be understood that these notonly accomplish certain methods but also can be varied in a number ofways. Importantly, as to all of the foregoing, all of these facetsshould be understood to be encompassed by this disclosure.

The discussion included in this application is intended to serve as abasic description. The reader should be aware that the specificdiscussion may not explicitly describe all embodiments possible; manyalternatives are implicit. It also may not fully explain the genericnature of the invention and may not explicitly show how each feature orelement can actually be representative of a broader function or of agreat variety of alternative or equivalent elements. Again, these areimplicitly included in this disclosure. Where the invention is describedin device-oriented terminology, each element of the device implicitlyperforms a function. Importantly, neither the description nor theterminology is intended to limit the scope of the claims which may beincluded at any time.

It should also be understood that a variety of changes may be madewithout departing from the essence of the invention. Such changes arealso implicitly included in the description. They still fall within thescope of this invention. A broad disclosure encompassing both theexplicit embodiment(s) shown, the great variety of implicit alternativeembodiments, and the broad methods or processes and the like areencompassed by this disclosure and may be relied upon at any time.

Further, each of the various elements of the invention and claims mayalso be achieved in a variety of manners. This disclosure should beunderstood to encompass each such variation, be it a variation of anembodiment of any apparatus embodiment, a method or process embodiment,or even merely a variation of any element of these. Particularly, itshould be understood that as the disclosure relates to elements of theinvention, the words for each element may be expressed by equivalentapparatus terms or method terms—even if only the function or result isthe same. Such equivalent, broader, or even more generic terms should beconsidered to be encompassed in the description of each element oraction. Such terms can be substituted where desired to make explicit theimplicitly broad coverage to which this invention is entitled. As butone example, it should be understood that all actions may be expressedas a means for taking that action or as an element which causes thataction. Similarly, each physical element disclosed should be understoodto encompass a disclosure of the action which that physical elementfacilitates. Regarding this last aspect, as but one example, thedisclosure of a “retention element” should be understood to encompassdisclosure of the act of “retaining”—whether explicitly discussed ornot—and, conversely, were there effectively disclosure of the act of“retaining”, such a disclosure should be understood to encompassdisclosure of a “retention element” and even a “means for retaining”. Itshould also be understood that in jurisdictions where specific languagemay be construed as limiting, as but one example in the United Stateswhere some interpretations of “means for” elements can be construednarrowly, broader equivalent language may be used and should beunderstood as encompassed by this specification. Such changes andalternative terms are to be understood to be explicitly included in thedescription.

Any patents, patent applications, publications, or other referencesmentioned in this application for patent are hereby incorporated byreference. In addition, as to each term used it should be understoodthat unless its utilization in this application is inconsistent withsuch interpretation, common dictionary definitions should be understoodas incorporated for each term and all definitions, alternative terms,and synonyms such as contained in the Random House Webster's UnabridgedDictionary, second edition are hereby incorporated by reference as wellas the definitions presented by searchStorage.com, such to be consideredas representing the meaning of the terms as understood by computerprofessionals. Finally, any priority case for this application is herebyappended and hereby incorporated by reference.

Thus, the applicant(s) should be understood to have support to claim atleast: i) each of the sample processing systems and subsystems as hereindisclosed and described, ii) the related methods disclosed anddescribed, iii) similar, equivalent, and even implicit variations ofeach of these systems, assemblies, devices and methods, iv) thosealternative designs which accomplish each of the functions shown as aredisclosed and described, v) those alternative designs and methods whichaccomplish each of the functions shown as are implicit to accomplishthat which is disclosed and described, vi) each feature, component, andstep shown as separate and independent inventions, vii) the applicationsenhanced by the various systems or components disclosed, viii) theresulting products produced by such systems or components, and ix)methods and systems, assemblies, devices, and apparatuses substantiallyas described hereinbefore and with reference to any of the accompanyingexamples, x) the various combinations and permutations of each of theelements disclosed, xi) each potentially dependent claim or concept as adependency on each and every one of the independent claims or conceptspresented, xii) processes performed with the aid of or on a computer asdescribed throughout the above discussion, xiii) a programmable systemas described throughout the above discussion, xiv) a computer readablememory encoded with data to direct a computer comprising means orelements which function as described throughout the above discussion,xv) a computer configured as herein disclosed and described, xvi)individual or combined subroutines and programs as herein disclosed anddescribed, xvii) the related methods disclosed and described, xviii)similar, equivalent, and even implicit variations of each of thesesystems and methods, xix) those alternative designs which accomplisheach of the functions shown as are disclosed and described, xx) thosealternative designs and methods which accomplish each of the functionsshown as are implicit to accomplish that which is disclosed anddescribed, xxi) each feature, component, and step shown as separate andindependent inventions, and xxii) the various combinations andpermutations of each of the above.

Further, if or when used, the use of the transitional phrase“comprising” or the like is used to maintain the “open-end” claimsherein, according to traditional claim interpretation. Thus, unless thecontext requires otherwise, it should be understood that the term“comprise” or variations such as “comprises” or “comprising” or thelike, are intended to imply the inclusion of a stated element or step orgroup of elements or steps but not the exclusion of any other element orstep or group of elements or steps. Such terms should be interpreted intheir most expansive form so as to afford the applicant the broadestcoverage legally permissible.

Any claims set forth at any time are hereby incorporated by reference aspart of this description of the invention, and the applicant expresslyreserves the right to use all of or a portion of such incorporatedcontent of such claims as additional description to support any of orall of the claims or any element or component thereof, and the applicantfurther expressly reserves the right to move any portion of or all ofthe incorporated content of such claims or any element or componentthereof from the description into the claims or vice-versa as necessaryto define the matter for which protection is sought by this applicationor by any subsequent continuation, division, or continuation-in-partapplication thereof, or to obtain any benefit of, reduction in feespursuant to, or to comply with the patent laws, rules, or regulations ofany country or treaty, and such content incorporated by reference shallsurvive during the entire pendency of this application including anysubsequent continuation, division, or continuation-in-part applicationthereof or any reissue or extension thereon.

1. A method of automated sample processing comprising the steps of:establishing an automated sample processing system having an automatedprocess operation capability that causes automated process operationevents through robotic sample process functions; scheduling a pluralityof sample process operations; systematically storing important detailsof a significant number of said plurality of sample process operationsas such sample process operations occur; automatically processing atleast one biological sample arranged on a slide at least in part throughoperation of said robotic sample process functions sequencing throughsaid scheduled plurality of sample process operations; monitoringoperationally-influential exteriorly-consequential information, whereinsaid step of monitoring operationally-influentialexteriorly-consequential information comprises the step of monitoringreplenishable supply information; automatically notifying at least oneperson of a potential need for a replenishable supply in response tosaid step of monitoring operationally-influentialexteriorly-consequential information; and replenishing saidreplenishable supply in real-time concurrently with sample processing.2. A method of automated sample processing as described in claim 1,further comprising the step of: automatically advance notifying at leastone person of information at least in part in response to said step ofmonitoring replenishable supply information.
 3. A method as described inclaim 2, wherein the replenishable supply comprises a buffer, a reagent,a stain, a target retrieval solution, an epitope retrieval solution, adeparaffinization fluid, or a combination thereof.
 4. A method ofautomated sample processing comprising the steps of: establishing anautomated sample processing system having an automated process operationcapability that causes automated process operation events throughrobotic sample process functions; scheduling a plurality of sampleprocess operations; systematically storing important details of asignificant number of said plurality of sample process operations assuch sample process operations occur; automatically processing at leastone biological sample arranged on a slide at least in part throughoperation of said robotic sample process functions sequencing throughsaid scheduled plurality of sample process operations; accepting aprompt from a user to display at least a portion of said importantdetails of a significant number of said plurality of sample processoperations; and providing information relative to said plurality ofsample process operations to at least one person, wherein said step ofsystematically storing important details of a significant number of saidplurality of sample process operations as sample process operationsoccur comprises the steps of: systematically storing time of occurrencedata, systematically storing substance identifier data, systematicallystoring individual robotic movement data, systematically storing subjectsample data, and systematically storing type of protocol data.
 5. Anautomated sample processing system comprising: a process operationcontrol system configured to at least partially process at least onebiological sample arranged on a slide; a robotic motion systemresponsive to said process operation control system; a multiple eventscheduler to which said robotic motion system is at least in partresponsive; a systematic process detail capture element; a significantprocess detail memory responsive to said systematic process detailcapture element and configured to store at least some significantprocess data; an operationally-influential exteriorly-consequentialinformation monitor comprising a replenishable supply informationmonitor configured to monitor replenishable supply information; anautomatic operator replenishable supply notice element that acts inresponse to said replenishable supply information monitor; and whereinsaid process operation control system is configured to allowreplenishing of said replenishable supply in real-time concurrently withsample processing.
 6. An automated sample processing system according toclaim 5, further comprising an automatic exteriorly-consequentialinformation advance notice element configured to automatically advancenotify at least one person of information at least in part in responseto said replenishable supply information monitor.
 7. An automated sampleprocessing system as described in claim 6, wherein the replenishablesupply comprises a buffer, a reagent, a stain, a target retrievalsolution, an epitope retrieval solution, a deparaffinization fluid, or acombination thereof.
 8. An automated sample processing systemcomprising: a process operation control system configured to at leastpartially process at least one biological sample arranged on a slide; arobotic motion system responsive to said process operation controlsystem; a multiple event scheduler to which said robotic motion systemis at least in part responsive; a systematic process detail captureelement; a significant process detail memory that is responsive to saidsystematic process detail capture element and that stores at least somesignificant process data; an information access prompt element to whichsaid significant process data is responsive; and a significant processdata transfer element, wherein said systematic process detail captureelement comprises: a time of occurrence data capture element, anindividual robotic movement data capture element, a substance identifierdata capture element, a subject sample data capture element, and a typeof protocol data capture element.